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Gold report 2014_jan23


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Gold report 2014_jan23

  3. 3. ii GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (UPDATED 2014) GOLDBOARDOFDIRECTORS(2013) MarcDecramer,MD,Chair KatholiekeUniversiteitLeuven Leuven,Belgium JorgenVestbo,MD,ViceChair OdenseUniversityHospital OdenseC,Denmark(and) UniversityofManchester,Manchester,UK JeanBourbeau,MD McGillUniversityHealthCentre Montreal,Quebec,Canada BartolomeR.Celli,MD BrighamandWomen’sHospital Boston,MassachusettsUSA DavidS.C.Hui,MD TheChineseUniversityofHongKong HongKong,ROC M.VictorinaLópezVarela,MD UniversidaddelaRepública Montevideo,Uruguay MasaharuNishimura,MD HokkaidoUniversitySchoolofMedicine Sapporo,Japan RobertoRodriguezRoisin,MD HospitalClínic,UniversityofBarcelona Barcelona,Spain RobertA.Stockley,MD UniversityHospitalsBirmingham Birmingham,UK ClausVogelmeier,MD UniversityofGießenandMarburg Marburg,Germany GOLDSCIENCEDIRECTOR SuzanneS.Hurd,PhD Vancouver,Washington,USA GOLDSCIENCECOMMITTEE*(2013) JørgenVestbo,MD,Chair HvidovreUniversityHospital,Hvidovre,Denmark andUniversityofManchester Manchester,England,UK AlvarG.Agusti,MD ThoraxInstitute,HospitalClinic Univ.Barcelona,Ciberes,Barcelona,Spain AntonioAnzueto,MD UniversityofTexasHealthScienceCenter SanAntonio,Texas,USA MarcDecramer,MD KatholiekeUniversiteitLeuven Leuven,Belgium LeonardoM.Fabbri,MD UniversityofModena&ReggioEmilia Modena,Italy PaulJones,MD StGeorge’sHospitalMedicalSchool London,England,UK FernandoMartinez,MD UniversityofMichiganSchoolofMedicine AnnArbor,Michigan,USA NicolasRoche,MD Hôtel-Dieu Paris,France RobertoRodriguez-Roisin,MD ThoraxInstitute,HospitalClinic Univ.Barcelona,Barcelona,Spain DonaldSin,MD St.Paul’sHospital Vancouver,Canada RobertStockley,MD UniversityHospital Birmingham,UK ClausVogelmeier,MD UniversityofGiessenandMarburg Marburg,Germany JadwigaA.Wedzicha,MD UnivCollegeLondon London,UK *DisclosureformsforGOLDCommitteesarepostedontheGOLDWebsite, COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  4. 4. iii GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (REVISED 2011) INVITEDREVIEWERS Joan-AlbertBarbera,MD HospitalClinic,UniversitatdeBarcelona BarcelonaSpain A.SoniaBuist,MD OregonHealthSciencesUniversity Portland,OR,USA PeterCalverley,MD UniversityHospitalAintree Liverpool,England,UK BartCelli,MD BrighamandWomen’sHospital Boston,MA,USA M.W.Elliott,MD St.James’sUniversityHospital Leeds,England,UK YoshinosukeFukuchi,MD JuntendoUniversity Tokyo,Japan MasakazuIchinose,MD WakayamaMedicalUniversity Kimiidera,Wakayama,Japan ChristineJenkins,MD WoolcockInstituteofMedicalResearch Camperdown.NSW,Australia H.A.M.Kerstjens,MD UniversityofGroningen Groningen,TheNetherlands PeterLange,MD HvidovreUniversityHospital Copenhagen,Denmark M.VictorinaLópezVarela,MD UniversidaddelaRepública Montevideo,Uruguay MariaMontesdeOca,MD HospitalUniversitariodeCaracas Caracas,Venezuela AtsushiNagai,MD TokyoWomen’sMedicalUniversity Tokyo,Japan DennisNiewoehner,MD VeteransAffairsMedicalCenter Minneapolis,MN,USA DavidPrice,MD UniversityofAberdeen Aberdeen,Scotland,UK NicolasRoche,MD,PhD UniversityParisDescartes Paris,France SanjaySethi,MD StateUniversityofNewYork Buffalo,NY,USA GOLDNATIONALLEADERS (SubmittingComments) LorenzoCorbetta,MD UniversityofFlorence Florence,Italy AlexandruCorlateanu,MD,PhD StateMedicalandPharmaceuticalUniversity RepublicofMoldova LeThiTuyetLan,MD,PhD UniversityofPharmacyandMedicine HoChiMinhCity,Vietnam FernandoLundgren,MD Pernambuco,Brazil E.M.Irusen,MD UniversityofStellenbosch SouthAfrica TimothyJ.MacDonald,MD St.Vincent’sUniversityHospital Dublin,Ireland TakahideNagase,MD UniversityofTokyo Tokyo,Japan EwaNizankowska-Mogilnicka,MD,PhD JagiellonianUniversityMedicalCollege Krakow,Poland MagvannorovOyunchimeg,MD Ulannbatar,Mongolia MostafizurRahman,MD NIDCH Mohakhali,Dhaka,Bangladesh COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  5. 5. iv PREFACE In 2011, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) released a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD. It recommended a major revision in the management strategy for COPD that was presented in the original 2001 document. Updated reports released in January 2013 and January 2014 are based on scientific literature published since the completion of the 2011 document but maintain the same treatment paradigm. Assessment of COPD is based on the patient’s level of symptoms, future risk of exacerbations, the severity of the spirometric abnormality, and the identification of comorbidities. The GOLD report is presented as a “strategy document” for health care professionals to use as a tool to implement effective management programs based on available health care systems. The quadrant management strategy tool is designed to be used in any clinical setting; it draws together a measure of the impact of the patient’s symptoms and an assessment of the patient’s risk of having a serious adverse health event in the future. More and more evidence is being produced to evaluate this strategy*. Evidence will continue to be evaluated by the GOLD committees and management strategy recommendations modified as required. GOLD has been fortunate to have a network of international distinguished health professionals from multiple disciplines. Many of these experts have initiated investigations of the causes and prevalence of COPD in their countries, and have developed innovative approaches for the dissemination and implementation of the GOLD management strategy. The GOLD initiative will continue to work with National Leaders and other interested health care professionals to bring COPD to the attention of governments, public health officials, health care workers, and the general public to raise awareness of the burden of COPD and to develop programs for early detection, prevention and approaches to management. We are most appreciative of the unrestricted educational grants from Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, Forest Laboratories, GlaxoSmithKline, Merck Sharp & Dohme, Mylan, Nonin Medical, Novartis, Pearl Therapeutics, Pfizer, Quintiles, and Takeda that enabled development of this report. Marc Decramer, MD Chair, GOLD Board of Directors Professor of Medicine Chief of the Respiratory Division University Hospital Katholieke Universiteit, Leuven Belgium Jørgen Vestbo, MD Vice-Chair, GOLD Board of Directors Chair, GOLD Science Committee Professor of Respiratory Medicine Odense University Hospital Odense, Denmark (and) The University of Manchester Manchester Academic Health Science University Hospital of South Manchester NHS Foundation Trust, Manchester, UK *Lange P, Marott JL, Vestbo J, Olsen KR, Ingebrigtsen TS, Dahl M, Nordestgaard BG. Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med. 2012 Nov 15;186(10):975-81. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  6. 6. v TABLE OF CONTENTS Preface.............................................................. .iv Methodology and Summary of New Recommendations viii Introduction.....................................................xiv 1. Definition and Overview 1 Key Points 2 Definition 2 Burden Of COPD 2 Prevalence 3 Morbidity 3 Mortality 3 Economic Burden 3 Social Burden 4 Factors That Influence Disease Development And Progression 4 Genes 4 Age and Gender 4 Lung Growth and Development 4 Exposure to Particles 5 Socioeconomic Status 5 Asthma/Bronchial Hyperreactivity 5 Chronic Bronchitis 5 Infections 5 Pathology, Pathogenesis And Pathophysiology 6 Pathology 6 Pathogenesis 6 Pathophysiology 6 2. Diagnosis and Assessment 9 Key Points 10 Diagnosis 10 Symptoms 11 Medical History 12 Physical Examination 12 Spirometry 12 Assessment Of Disease 12 Assessment of Symptoms 13 Choice of Cut Points 13 Spirometric Assessment 14 Assessment of Exacerbation Risk 14 Assessment of Comorbidities 15 Combined COPD Assessment 15 Additional Investigations 16 Differential Diagnosis 17 3. Therapeutic Options 19 Key Points 20 Smoking Cessation 20 Pharmacotherapies for Smoking Cessation 20 Pharmacologic Therapy for Stable COPD 21 Overview of the Medications 21 Bronchodilators 21 Corticosteroids 24 Phosphodiesterase-4 Inhibitors 25 Other Pharmacologic Treatments 25 Non-Pharmacologic Therapies 26 Rehabilitation 26 Components of Pulmonary Rehabilitation Programs 27 Other Treatments 28 Oxygen Therapy 28 Ventilatory Support 29 Surgical Treatments 29 Palliative Care, End-of-life Care, Hospice Care 29 4. Management of Stable COPD 31 Key Points 32 Introduction 32 Identify And Reduce Exposure to Risk Factors 33 Tobacco Smoke 33 Occupational Exposures 33 Indoor And Outdoor Pollution 33 Treatment of Stable COPD 33 Moving from Clinical Trials to Recommendations for Routine Practice Considerations 33 Non-Pharmacologic Treatment 34 Smoking Cessation 34 Physical Activity 34 Rehabilitation 34 Vaccination 34 Pharmacologic Treatment 35 Bronchodilators - Recommendations 35 Corticosteroids and Phosphodiesterase-4 Inhibitors - Recommendations 37 Monitoring And Follow-Up 37 Monitor Disease Progression and Development of Complications 37 Monitor Pharmacotherapy and Other Medical Treatment 37 COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  7. 7. vi Monitor Exacerbation History 37 Monitor Comorbidities 37 Surgery in the COPD Patient 38 5. Management of Exacerbations 39 Key Points 40 Definition 40 Diagnosis 40 Assessment 41 Treatment Options 41 Treatment Setting 41 Pharmacologic Treatment 41 Respiratory Support 43 Hospital Discharge and Follow-up 44 Home Management of Exacerbations 45 Prevention of COPD Exacerbations 45 6. COPD and Comorbidities 47 Key Points 48 Introduction 48 Cardiovascular Disease 48 Osteoporosis 49 Anxiety and Depression 50 Lung Cancer 50 Infections 50 Metabolic Syndrome and Diabetes 50 Bronchiectasis 50 7. Asthma & COPD Overlap Syndrome (ACOS) 51 References 53 Figures Figure 1.1. Mechanisms Underlying Airflow Limitation in COPD 2 Figure 2.1A. Spirometry - Normal Trace 13 Figure 2.1B. Spirometry - Obstructive Disease 13 Figure 2.2. Relationship Between Health-Related Quality of Life, Post-Bronchodilator FEV1 and GOLD Spirometric Classification 14 Figure 2.3. Association Between Symptoms, Spirometric Classification and Future Risk of Exacerbations 15 Tables Table A. Description of Levels of Evidence  xvi Table 2.1. Key Indicators for Considering a Diagnosis of COPD 10 Table 2.2. Causes of Chronic Cough 11 Table 2.3. Considerations in Performing Spirometry 12 Table 2.4. Modified Medical Research Council Questionnaire for Assessing the Severity of Breathlessness 13 Table 2.5. Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV1 ) 14 Table 2.6. RISK IN COPD: Placebo-limb data from TORCH, Uplift, and Eclipse 15 Table 2.7. COPD and its Differential Diagnoses 18 Table 3.1. Treating Tobacco Use and Dependence: A Clinical Practice Guideline—Major Findings and Recommendations 20 Table 3.2. Brief Strategies to Help the Patient Willing to Quit 21 Table 3.3. Formulations and Typical Doses of COPD Medications 22 Table 3.4. Bronchodilators in Stable COPD 23 Table 3.5. Benefits of Pulmonary Rehabilitation in COPD 26 Table 4.1. Goals for Treatment of Stable COPD 32 Table 4.2. Model of Symptom/Risk of Evaluation of COPD 33 Table 4.3. Non-pharmacologic Management of COPD 34 Table 4.4. Initial Pharmacologic Management of COPD 36 Table 5.1. Assessment of COPD Exacerbations: Medical History 41 Table 5.2. Assessment of COPD Exacerbations: Signs of Severity 41 Table 5.3. Potential Indications for Hospital Assessment or Admission 41 Table 5.4. Management of Severe but Not Life-Threatening Exacerbations 42 Table 5.5. Therapeutic Components of Hospital Management 42 Table 5.6. Indications for ICU Admission 43 Table 5.7. Indications for Noninvasive Mechanical Ventilation 43 COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  8. 8. vii Table 5.8. Indications for Invasive Mechanical Ventilation 43 Table 5.9. Discharge Criteria 44 Table 5.10. Checklist of items to assess at time of Discharge from Hospital 44 Table 5.11. Items to Assess at Follow-Up Visit 4-6 Weeks After Discharge from Hospital 44 COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  9. 9. viii METHODOLOGY AND SUMMARY OF NEW RECOMMENDATIONS GLOBAL STRATEGY FOR DIAGNOSIS, MANAGEMENT AND PREVENTION OF COPD 2014 UPDATE1 When the Global Initiative for Chronic Obstructive Lung Disease (GOLD) program was initiated in 1998, a goal was to produce recommendations for management of COPD based on the best scientific information available. The first report, Global Strategy for Diagnosis, Management and Prevention of COPD was issued in 2001. In 2006 and again in 2011 a complete revision was prepared based on published research. These reports, and their companion documents, have been widely distributed and translated into many languages and can be found on the GOLD website ( The GOLD Science Committee2 was established in 2002 to review published research on COPD management and prevention, to evaluate the impact of this research on recommendations in the GOLD documents related to management and prevention, and to post yearly updates on the GOLD website. Its members are recognized leaders in COPD research and clinical practice with the scientific credentials to contribute to the task of the Committee and are invited to serve in a voluntary capacity. The first update of the 2011 revised report was released in January 2013. This second update, released January 2014, is based on the impact of publications from January 1 through December 31, 2013. Posted on the website along with the updated documents is a list of all the publications reviewed by the Committee. Process: To produce the updated documents a Pub Med search is completed using search fields established by the Committee: 1) COPD, All Fields, All Adult: 19+ years, only items with abstracts, Clinical Trial, Systematic Reviews, Human. The first search included publications for January 1 – March 31 for review by the Committee during the ATS meeting. The second search included publications for April 1 – August 31 for review by the Committee during the ERS meeting. The third search for publications from September – December were reviewed in December by the GOLD Board of Directors. Publications in peer review journals not captured by Pub Med can be submitted to the Chair, GOLD Science Committee, providing an abstract and the full paper are submitted in (or translated into) English. Members of the Committee receive a summary of citations and all abstracts. Each abstract is assigned to two Committee members, although all members are offered the opportunity to provide an opinion on any abstract. Members evaluate the abstract or, up to her/his judgment, the full publication, by answering four specific written questions from a short questionnaire, and to indicate if the scientific data presented impacts on recommendations in the GOLD report. If so, the member is asked to specifically identify modifications that should be made. The GOLD Science Committee meets twice yearly to discuss each publication that was considered by at least 1 member of the Committee to potentially have an impact on the COPD management. The full Committee then reaches a consensus on whether to include it in the report, either as a reference supporting current recommendations, or to change the report. In the absence of consensus, disagreements are decided by an open vote of the full Committee. The final review and approval of all recommendations is provided by the GOLD Board of Directors at its annual meeting in December. Recommendations by the GOLD Committees for use of any medication are based on the best evidence available from the published literature and not on labeling directives from government regulators. The Committee does not make recommendations for therapies that have not been approved by at least one regulatory agency. 1 The Global Strategy for Diagnosis, Management and Prevention of COPD (updated 2014), the Pocket Guide (updated 2014) and the complete list of references examined by the Committee are available on the GOLD website 2 Members (2012-2013): J. Vestbo, Chair; A. Agusti, A. Anzueto, L. Fabbri, P. Jones, F. Martinez, N. Roche, R. Rodriguez-Roisin, D. Sin, R. Stockley, C. Volgelmeier, W. Wedzicha. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  10. 10. ix As an example of the workload of the Committee, for the 2014 update, between January and December, 2013, 292 articles met the search criteria. Of the 292 papers, 30 were identified to have an impact on the GOLD report posted on the website in January 2014 either by: A) modifying, that is, changing the text or introducing a concept requiring a new recommendation to the report; B) confirming, that is, adding or replacing an existing reference; or C) requiring modification for clarification of the text. SUMMARY OF RECOMMENDATIONS IN THE 2014 UPDATE A. Additions to the text Page 17, left column, last paragraph line 5, insert statement and reference: Exercise capacity may fall in the year before death557. Reference 557: Polkey MI, Spruit MA, Edwards LD, Watkins ML, Pinto-Plata V, Vestbo J, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study Investigators. Six-minute-walk test in chronic obstructive pulmonary disease: minimal clinically important difference for death or hospitalization. Am J Respir Crit Care Med 2013 Feb 15;187(4):382-6. Page 23, right column, second paragraph, replace sentence on line 13 beginning with “Tiotropium has…” with: Among long-acting anticholinergics, acclidinium has a duration of at least 12 hours552 whereas tiotropium and glycopyrronium have a duration of action of more than 24 hours209-211 . Reference 552: Jones PW, Singh D, Bateman ED, Agusti A, Lamarca R, de Miquel G,Segarra R, Caracta C, Garcia Gil E. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012 Oct;40(4):830-6. Page 23, right column, second paragraph, insert statement and reference at the end: The long-acting anticholinergics aclidinium and glycopyrronium seem to have similar action on lung function and breathlessness as tiotropium, whereas far less data are available for other outcomes552, 558 . Reference 552: Jones PW, Singh D, Bateman ED, Agusti A, Lamarca R, de Miquel G, Segarra R, Caracta C, Garcia Gil E. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012 Oct;40(4):830-6. Reference 558: Kerwin E, Hébert J, Gallagher N, Martin C, Overend T, Alagappan VK, Lu Y, Banerji D. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J 2012 Nov;40(5):1106-14. Page 24, left column, first paragraph, replace section beginning with “Tiotropium delivered…” to end of paragraph with: Tiotropium delivered via the Respimat® soft mist inhaler was associated with a significantly increased risk of mortality compared with placebo in a meta-analysis519 ; however, the findings of the TIOSPIR® trial showed that there was no difference in mortality or rates of exacerbation when comparing tiotropium in a dry-powder inhaler to the Respimat® inhaler559 . Use of solutions with a facemask has been reported to precipitate acute glaucoma, probably by a direct effect of the solution on the eye. Reference 559: Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al for the TIOSPIR Investigators. Tiotripium Respimat Inhaler and the Risk of Death in COPD. N Engl J Med 2013 Oct 17;369(16):1491-1501. Page 24, right column, end of second paragraph, insert statement and references: Combinations of a long-acting beta2 -agonist and a long-acting anticholinergic have shown a significant increase in lung function whereas the impact on patient reported outcomes is still limited560 . There is still too little evidence to determine if a combination of long-acting bronchodilators is more effective than a long-acting anticholinergic alone for preventing exacerbations561 . Reference 560: Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013 Dec;42(6):1484-94. Reference 561: Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, SandstroÅNm T, Taylor AF, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1:199–209  COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  11. 11. x Page 26, right column, end of last paragraph, insert statement and reference: However the increased exercise capacity may not necessarily translate into increased daily physical activity563 . Reference 563: Egan C, Deering BM, Blake C, Fullen BM, McCormack NM, Spruit MA, Costello RW. Short term and long term effects of pulmonary rehabilitation on physical activity in COPD. Respir Med 2012 Dec;106(12):1671-9. Page 28, right column, second paragraph, replace heading Nutrition counseling by Nutritional support. Replace two paragraphs with statement and reference: Low-to-moderate quality evidence suggests that nutritional support promotes significant gain in weight and fat-free mass among patients with COPD, especially if malnourished. In addition, significantly greater changes from baseline have been observed in supplemented patients for six-minute walk test, respiratory muscle strength and (only in malnourished patients) overall HRQoL as measured by SGRQ. Positive effects have been observed when nutritional supplementation is proposed alone or as an adjunct to exercise training. The optimal amount and duration of supplementation are not clearly established564 . Reference 564: Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012 Dec 12;12:CD000998. Page 35, left column, third paragraph line four, modify sentence to read: However, for all Group A patients, a short-acting bronchodilator used as needed is recommended as first choice based on its effect on lung function and breathlessness565 . Reference 565: Gagnon P, Saey D, Provencher S, Milot J, Bourbeau J, Tan WC, Martel S, Maltais F. Walking exercise response to bronchodilation in mild COPD: a randomized trial. Respir Med 2012 Dec;106(12):1695-705. Page 37, left column, end of first paragraph under monitoring and follow up, insert statement and reference: Comprehensive self-management or routine monitoring does not appear to show long term benefits in terms of quality of life or self efficacy over usual care alone in COPD patients in general practice566 . Reference 566: Bischoff EW, Akkermans R, Bourbeau J, van Weel C, Vercoulen JH, Schermer TR. Comprehensive self management and routine monitoring in chronic obstructive pulmonary disease patients in general practice: randomised controlled trial. BMJ 2012 Nov 28;345:e7642. Page 42, right column, first line delete “A dose of 30-40 mg prednisone per day for 10-14 days is recommended (Evidence D), and insert: A dose of 40 mg prednisone per day for 5 days is recommended (Evidence B)567 . Reference 567: Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, et al.. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013 Jun 5;309(21):2223-31. Page 42, right column, insert at the end of first paragraph: Nebulised magnesium as an adjuvant to salbutamol treatment in the setting of acute exacerbations of COPD has no effect on FEV1 568 . Reference 568: Edwards L, Shirtcliffe P, Wadsworth K, Healy B, Jefferies S, Weatherall M, Beasley R; Magnesium COPD Study Team. Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial. Thorax 2013 Apr;68(4):338-43. Page 43 at end of paragraph on Adjunct Therapies, insert statement and references; Given that patients hospitalized because of exacerbations of COPD are at increased risk of deep vein thrombosis and pulmonary embolism570,571 , thromboprophylactic measures should be enhanced572-574 . Reference 570: Rizkallah J, Man SF, Sin DD. Prevalence of pulmonary embolism in exacerbations of COPD: a systematic review and metaanalysis. Chest 2009 Mar;135(3):786-93. Reference 571: Gunen H, Gulbas G, In E, Yetkin O, Hacievliyagil SS. Venous thromboemboli and  exacerbations of COPD. Eur Respir J 2010;35(6):1243-8. Reference 572: Qaseem A, Chou R, Humphrey LL, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Venous thromboembolism prophylaxis in hospitalized patients: COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  12. 12. xi a clinical practice guideline from the American College of Physicians. Ann Intern Med 2011 Nov 1;155(9):625-32. Reference 573: Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e195S- 226S. Reference 574: Bertoletti L, Quenet S, Laporte S, Sahuquillo JC, Conget F, Pedrajas JM, Martin M, Casado I, Riera-Mestre A, Monreal M; RIETE Investigators. Pulmonary embolism and 3-month outcomes in 4036 patients with venous thromboembolism and chronic obstructive pulmonary disease: data from the RIETE registry. Respir Res 2013 Jul 18;14:75. Page 45, left column, last sentence under Home Management of Exacerbations, insert statement and three references: Accumulating data from a variety of studies indicate that telehealth in any of its current forms has not shown benefits for patients with COPD; thus, telehealth is not recommended for use with COPD patients575-577 . Reference 575: Cartwright M, Hirani SP, Rixon L, Beynon M, Doll H, Bower P, et al; Whole Systems Demonstrator Evaluation Team. Effect of telehealth on quality of life and psychological outcomes over 12 months (Whole Systems Demonstrator telehealth questionnaire study): nested study of patient reported outcomes in a pragmatic, cluster randomised controlled trial. BMJ 2013 Feb 26;346:f653. Reference 576: Henderson C, Knapp M, Fernández JL, Beecham J, Hirani SP, Cartwright M, et al; Whole System Demonstrator evaluation team. Cost effectiveness of telehealth for patients with long term conditions (Whole Systems Demonstrator telehealth questionnaire study): nested economic evaluation in a pragmatic, cluster randomised controlled trial. BMJ 2013 Mar 20;346:f1035. Reference 577: Pinnock H, Hanley J, McCloughan L, Todd A, Krishan A, Lewis S, et al. Effectiveness of telemonitoring integrated into existing clinical services on hospital admission for exacerbation of chronic obstructive pulmonary disease: researcher blind, multicentre, randomised controlled trial. BMJ 2013 Oct 17;347:f6070. Page 50, insert at end of chapter on COPD and Comorbidities: Bronchiectasis: Persistent airflow obstruction is a recognized feature of some patients with a primary diagnosis of bronchiectasis. However with increasing use of computed tomography in the assessment of patients with COPD, the presence of previously unrecognized radiographic bronchiectasis is being identified581 . This ranges from mild tubular bronchiectasis to more severe varicose change, although cystic bronchiectasis is uncommon. Whether this radiological change has the same impact as patients with a primary diagnosis of bronchiectasis remains unknown at present, although it is associated with longer exacerbations582 and increased mortality583 . Treatment of bronchiectasis in patients with COPD: Treatment should be along conventional lines for bronchiectasis with the addition of usual COPD strategies where indicated. Whether prevention of exacerbations requires more long-term use of oral or inhaled antibiotics rather than bronchodilator or inhaled corticosteroid therapy remains unknown. Treatment of COPD in patients with bronchiectasis: COPD should be treated as usual, although some patients may need more aggressive and prolonged antibiotic therapy. Reference 581: O’Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000;558:635-642 Reference 582: Patel IS, Vlahos I, Wilkinson TMA, et al. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;1704:400- 407 Reference 583: Martínez-García MA, de la Rosa Carrillo D, Soler-Cataluña JJ, Donat-Sanz Y, Serra PC, Lerma MA, Ballestín J, Sánchez IV, Selma Ferrer MJ, Dalfo AR, Valdecillos MB. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013 Apr 15;187(8):823-31 COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  13. 13. xii B. References that provided confirmation or update of previous recommendations Page 26, left column, line 11, after reference 297, insert: Reference 562: Tse HN, Raiteri L, Wong KY, Yee KS, Ng LY, Wai KY, Loo CK, Chan MH. High-dose N-acetylcysteine in stable COPD: the 1-year, double- blind, randomized, placebo-controlled HIACE study. Chest 2013 Jul;144(1):106-18. Page 42, right column, end of first sentence under paragraph on Antibiotics, insert: Reference 569: Vollenweider DJ, Jarrett H, Steurer- Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012 Dec 12;12:CD010257. Page 42, right column, line 5 from end, insert after reference 273: Reference 351: Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196- 204. Page 48 after reference 476 in first sentence insert: Reference 578: Almagro P, Cabrera FJ, Diez J, Boixeda R, Alonso Ortiz MB, Murio C, Soriano JB; Working Group on COPD, Spanish Society of Internal Medicine. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest 2012 Nov;142(5):1126-33. Pages 48 right column, paragraph 4 after reference 546 and Page 49 left column after reference 481 insert: Reference 579: Mainguy V, Girard D, Maltais F, Saey D, Milot J, Sénéchal M, Poirier P, Provencher S. Effect of bisoprolol on respiratory function and exercise capacity in chronic obstructive pulmonary disease. Am J Cardiol 2012 Jul 15;110(2):258-63 Reference 580: Stefan MS, Rothberg MB, Priya A, Pekow PS, Au DH, Lindenauer PK. Association between β-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. Thorax 2012 Nov;67(11):977-84. C. Modifications to text to correct wording Page 35, right column, paragraph 2, second and third sentence should read: The first choice of therapy is inhaled corticosteroid plus long-acting beta2- agonist or long-acting anticholinergic, although there are conflicting findings concerning this treatment257 ; support for it mainly comes from short-term studies257,538,539 (Evidence B). As second choice a combination of all three classes of drugs (inhaled corticosteroids/long-acting beta2 -agonist/long-acting anticholinergic) is recommended256 . D. Inserts related to tables/figures and special topics covered by the Committee PREFACE, page iv: A new Preface includes a statement about the quadrant management strategy. Page 13, left column: The material on Assessment of Symptoms has been modified and several new references inserted. Page 14, right column: The material on Assessment of Exacerbation Risk has been modified and one new reference inserted. Page 15, right column: Figure 2.3 has been modified to reflect the new statement on page 13 related to Assessment of Symptoms. Page 15, right column and page 16 left column: Text has been modified to reflect the new statements on page 13 related to Assessment of Symptoms. Page 22, Table 3.3. Formulations and Typical Doses of COPD Medications, insert under heading Combination long-acting beta2-agonists plus corticosteroids in one inhaler: Vilanterol/Fluticasone furoate, 25/100 (DPI). Page 33, left column: Table 4.2 has been modified to reflect the new statement on page 13 related to Assessment of Symptoms. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  14. 14. xiii Page 51 Insert Chapter 7: Asthma and COPD Overlap Syndrome (ACOS) A chapter on Asthma and COPD Overlap Syndrome (ACOS) is in preparation by the Science Committees of the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD). It is expected to be available with the release of the GINA 2014 document Global Strategy for Asthma Management and Prevention in the Spring 2014. A brief summary is included in this 2014 GOLD update; the full chapter will be posted on the GOLD website when it is available, and will appear in full in the 2015 GOLD update. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  15. 15. xiv GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD Much has changed in the 10 years since the first GOLD report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, was published. This major revision builds on the strengths from the original recommendations and incorporates new knowledge. One of the strengths was the treatment objectives. These have stood the test of time, but are now organized into two groups: objectives that are directed towards immediately relieving and reducing the impact of symptoms, and objectives that reduce the risk of adverse health events that may affect the patient at some point in the future. (Exacerbations are an example of such events.) This emphasizes the need for clinicians to maintain a focus on both the short-term and long-term impact of COPD on their patients. A second strength of the original strategy was the simple, intuitive system for classifying COPD severity. This was based upon the FEV1 and was called a staging system because it was believed, at the time, that the majority of patients followed a path of disease progression in which the severity of the disease tracked the severity of the airflow limitation. Much is now known about the characteristics of patients in the different GOLD stages – for example, their level of risk of exacerbations, hospitalization, and death. However at an individual patient level, the FEV1 is an unreliable marker of the severity of breathlessness, exercise limitation, and health status impairment. This report retains the GOLD classification system because it is a predictor of future adverse events, but the term “Stage” is now replaced by “Grade.” At the time of the original report, improvement in both symptoms and health status was a GOLD treatment objective, but symptoms assessment did not have a direct relation to the choice of management, and health status measurement was a complex process largely confined to clinical studies. Now, there are simple and reliable questionnaires designed for use in routine daily clinical practice. These are available in many languages. These developments have enabled a new assessment system to be developed that draws together a measure of the impact of the patient’s symptoms and an assessment of the patient’s risk of having a serious adverse health event in the future. In turn, this new assessment system has led to the construction of a new approach to management– one that matches assessment to treatment objectives. The new management approach can be used in any clinical setting anywhere in the world and moves COPD treatment towards individualized medicine – matching the patient’s therapy more closely to his or her needs. Chronic Obstructive Pulmonary Disease (COPD), the fourth leading cause of death in the world1 , represents an important public health challenge that is both preventable and treatable. COPD is a major cause of chronic morbidity and mortality throughout the world; many people suffer from this disease for years, and die prematurely from it or its complications. Globally, the COPD burden is projected to increase in coming decades because of continued exposure to COPD risk factors and aging of the population2 . In 1998, with the cooperation of the National Heart, Lung, and Blood Institute, NIH and the World Health Organization, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was implemented. Its goals were to increase awareness of the burden of COPD and to improve prevention and management of COPD through a concerted worldwide effort of people involved in all facets of health care and health care policy. An important and related goal was to encourage greater research interest in this highly prevalent disease. In 2001, GOLD released it first report, Global Strategy for the Diagnosis, Management, and Prevention of COPD. This report was not intended to be a comprehensive textbook on COPD, but rather to summarize the current state of the field. It was developed by individuals with expertise in COPD research and patient care and was based on the best-validated concepts of COPD pathogenesis at that time, along with available evidence on the most appropriate management and prevention strategies. It provided state-of- the-art information about COPD for pulmonary specialists and other interested physicians and served as a source document for the production of various communications for other audiences, including an Executive Summary3 , a Pocket Guide for Health Care Professionals, and a Patient Guide. Immediately following the release of the first GOLD report in 2001, the GOLD Board of Directors appointed a Science Committee, charged with keeping the GOLD documents up-to-date by reviewing published research, evaluating the impact of this research on the management INTRODUCTION BACKGROUND COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  16. 16. xv recommendations in the GOLD documents, and posting yearly updates of these documents on the GOLD Website. The first update to the GOLD report was posted in July 2003, based on publications from January 2001 through December 2002. A second update appeared in July 2004, and a third in July 2005, each including the impact of publications from January through December of the previous year. In January 2005, the GOLD Science Committee initiated its work to prepare a comprehensively updated version of the GOLD report; it was released in 2006. The methodology used to create the annual updated documents, and the 2006 revision, appears at the front of each volume. During the period from 2006 to 2010, again annual updated documents were prepared and released on the GOLD Website, along with the methodology used to prepare the documents and the list of published literature reviewed to examine the impact on recommendations made in the annual updates. In 2009, the GOLD Science Committee recognized that considerable new information was available particularly related to diagnosis and approaches to management of COPD that warranted preparation of a significantly revised report. The work on this new revision was implemented in mid-2009 while at the same time the Committee prepared the 2010 update. In September 2009 and in May and September 2010 while preparing the annual updated reports (http://www.goldcopd. org), Science Committee members began to identify the literature that impacted on major recommendations, especially for COPD diagnosis and management. Committee members were assigned chapters to review for proposed modifications and soon reached consensus that the report required significant change to reach the target audiences – the general practitioner and the individuals in clinics around the world who first see patients who present with respiratory symptoms that could lead to a diagnosis of COPD. In the summer of 2010 a writing committee was established to produce an outline of proposed chapters, which was first presented in a symposium for the European Respiratory Society in Barcelona, 2010. The writing committee considered recommendations from this session throughout fall 2010 and spring 2011. During this period the GOLD Board of Directors and GOLD National Leaders were provided summaries of the major new directions recommended. During the summer of 2011 the document was circulated for review to GOLD National Leaders, and other COPD opinion leaders in a variety of countries. The names of the individuals who submitted reviews appear in the front of this report. In September 2011 the GOLD Science Committee reviewed the comments and made final recommendations. The report was launched during a symposium hosted by the Asian Pacific Society of Respirology in November 2011. 1. This document has been considerably shortened in length by limiting to Chapter 1 the background information on COPD. Readers who wish to access more comprehensive information about the pathophysiology of COPD are referred to a variety of excellent textbooks that have appeared in the last decade. 2. Chapter 2 includes information on diagnosis and assessment of COPD. The definition of COPD has not been significantly modified but has been reworded for clarity. 3. Assessment of COPD is based on the patient’s level of symptoms, future risk of exacerbations, the severity of the spirometric abnormality, and the identification of comorbidities. Whereas spirometry was previously used to support a diagnosis of COPD, spirometry is now required to make a confident diagnosis of COPD. 4. The spirometric classification of airflow limitation is divided into four Grades (GOLD 1, Mild; GOLD 2, Moderate; GOLD 3, Severe; and GOLD 4, Very Severe) using the fixed ratio, postbronchodilator FEV1 /FVC < 0.70, to define airflow limitation. It is recognized that use of the fixed ratio (FEV1 /FVC) may lead to more frequent diagnoses of COPD in older adults with mild COPD as the normal process of aging affects lung volumes and flows, and may lead to under- diagnosis in adults younger than 45 years. The concept of staging has been abandoned as a staging system based on FEV1 alone was inadequate and the evidence for an alternative staging system does not exist. The most severe spirometric Grade, GOLD 4, does not include reference to respiratory failure as this seemed to be an arbitrary inclusion. 5. A new chapter (Chapter 3) on therapeutic approaches has been added. This includes descriptive information on both pharmacologic and non-pharmacologic therapies, identifying adverse effects, if any. 6. Management of COPD is presented in three chapters: Management of Stable COPD (Chapter 4); Management of COPD Exacerbations (Chapter 5); and COPD and Comorbidities (Chapter 6), covering both management of comorbidities in patients with COPD and of COPD in patients with comorbidities. 7. In Chapter 4, Management of Stable COPD, recommended approaches to both pharmacologic and non-pharmacologic treatment of COPD are presented. The chapter begins with the importance of identification and reduction of risk factors. Cigarette smoke continues to be METHODOLOGY NEW ISSUES PRESENTED IN THIS REPORT COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  17. 17. xvi identified as the most commonly encountered risk factor for COPD and elimination of this risk factor is an important step toward prevention and control of COPD. However, more data are emerging to recognize the importance of other risk factors for COPD that should be taken into account where possible. These include occupational dusts and chemicals, and indoor air pollution from biomass cooking and heating in poorly ventilated dwellings – the latter especially among women in developing countries. 8. In previous GOLD documents, recommendations for management of COPD were based solely on spirometric category. However, there is considerable evidence that the level of FEV1 is a poor descriptor of disease status and for this reason the management of stable COPD based on a strategy considering both disease impact (determined mainly by symptom burden and activity limitation) and future risk of disease progression (especially of exacerbations) is recommended. 9. Chapter 5, Management of Exacerbations, presents a revised definition of a COPD exacerbation. 10. Chapter 6, Comorbidities and COPD, focuses on cardiovascular diseases, osteoporosis, anxiety and depression, lung cancer, infections, and metabolic syndrome and diabetes. Levels of evidence are assigned to management recommendations where appropriate. Evidence levels are indicated in boldface type enclosed in parentheses after the relevant statement e.g., (Evidence A). The methodological issues concerning the use of evidence from meta-analyses were carefully considered. This evidence level scheme (Table A) has been used in previous GOLD reports, and was in use throughout the preparation of this document4 . Table A. Description of Levels of Evidence Evidence Catagory Sources of Evidence Definition A Randomized controlled trials (RCTs). Rich body of data. Evidence is from endpoints of well-designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants. B Randomized controlled trials (RCTs). Limited body of data. Evidence is from endpoints of intervention studies that include only a limited number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent. C Nonrandomized trials. Observational studies. Evidence is from outcomes of uncontrolled or nonrandomized trials or from observational studies D Panel Consensus Judgment. This category is used only in cases where the provision of some guidance was deemed valuable but the clinical literature addressing the subject was deemed insufficient to justify placement in one of the other categories. The Panel Consensus is based on clinical experience or knowledge that does not meet the above-listed criteria LEVELS OF EVIDENCE COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  19. 19. 2 DEFINITION AND OVERVIEW KEY POINTS: • Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. • COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. • Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic inflammatory response may induce parenchymal tissue destruction (resulting in emphysema), and disrupt normal repair and defense mechanisms (resulting in small airway fibrosis). These pathological changes lead to air trapping and progressive airflow limitation, and in turn to breathlessness and other characteristic symptoms of COPD. Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airways disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person (Figure 1.1). Chronic inflammation causes structural changes and narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory processes, leads to the loss of alveolar attachments to the small airways and decreases lung elastic recoil; in turn, these changes diminish the ability of the airways to remain open during expiration. Airflow limitation is best measured by spirometry, as this is the most widely available, reproducible test of lung function. Many previous definitions of COPD have emphasized the terms “emphysema” and “chronic bronchitis,” which are not included in the definition used in this or earlier GOLD reports. Emphysema, or destruction of the gas-exchanging surfaces of the lung (alveoli), is a pathological term that is often (but incorrectly) used clinically and describes only one of several structural abnormalities present in patients with COPD. Chronic bronchitis, or the presence of cough and sputum production for at least 3 months in each of two consecutive years, remains a clinically and epidemiologically useful term. However, it is important to recognize that chronic cough and sputum production (chronic bronchitis) is an independent disease entity that may precede or follow the development of airflow limitation and may be associated with development and/ or acceleration of fixed airflow limitation. Chronic bronchitis also exists in patients with normal spirometry. COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing2,5 . COPD prevalence, morbidity, and mortality vary across countries and across different groups within countries. COPD is the result of cumulative exposures over decades. Often, the prevalence of COPD is directly related to the prevalence of tobacco smoking, although in many countries, outdoor, occupational and indoor air pollution – the latter resulting from the burning of wood and other biomass fuels – are major COPD risk factors6 . The prevalence and burden of COPD are projected to increase in the coming decades due to continued exposure to COPD risk factors and the changing age structure of the world’s population (with more people living longer and therefore expressing the long-term effects of exposure to COPD risk factors)5 . Information on the burden of COPD can be found on international CHAPTER 1: DEFINITION AND OVERVIEW DEFINITION BURDEN OF COPD Figure 1.1. Mechanisms Underlying Airflow Limitation in COPD Small airways disease Airway inflammation Airway fibrosis; luminal plugs Increased airway resistance Parenchymal destruction Loss of alveolar attachments Decrease of elastic recoil AIRFLOW LIMITATION COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  20. 20. DEFINITION AND OVERVIEW 3 Websites such as those of the World Health Organization (WHO) ( and the World Bank/WHO Global Burden of Disease Study ( global_burden_of_disease). Aging itself is a risk factor for COPD and aging of the airways and parenchyma mimic some of the structural changes associated with COPD7 . Prevalence Existing COPD prevalence data show remarkable variation due to differences in survey methods, diagnostic criteria, and analytic approaches8 . The lowest estimates of prevalence are those based on self-reporting of a doctor diagnosis of COPD or equivalent condition. For example, most national data show that less than 6% of the adult population has been told that they have COPD8 . This likely reflects the widespread under-recognition and under- diagnosis of COPD9 . Despite the complexities, data are emerging that enable some conclusions to be drawn regarding COPD prevalence, not least because of increasing data quality control. A systematic review and meta-analysis of studies carried out in 28 countries between 1990 and 20048 , and an additional study from Japan10 , provide evidence that the prevalence of COPD is appreciably higher in smokers and ex-smokers than in nonsmokers, in those over 40 years of age than those under 40, and in men than in women. The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO)11 examined the prevalence of post-bronchodilator airflow limitation among persons over age 40 in five major Latin American cities, each in a different country – Brazil, Chile, Mexico, Uruguay, and Venezuela. In each country, the prevalence of COPD increased steeply with age, with the highest prevalence among those over age 60, ranging in the total population from a low of 7.8% in Mexico City, Mexico to a high of 19.7% in Montevideo, Uruguay. In all cities/countries the prevalence was appreciably higher in men than in women11 , which contrasts with findings from European cities such as Salzburg12 . The Burden of Obstructive Lung Diseases program (BOLD) has carried out surveys in several parts of the world13 and has documented more severe disease than previously found and a substantial prevalence (3-11%) of COPD among never-smokers. Morbidity Morbidity measures traditionally include physician visits, emergency department visits, and hospitalizations. Although COPD databases for these outcome parameters are less readily available and usually less reliable than mortality databases, the limited data available indicate that morbidity due to COPD increases with age10-12 . Morbidity from COPD may be affected by other comorbid chronic conditions (e.g., cardiovascular disease, musculoskeletal impairment, diabetes mellitus) that are related to COPD and may have an impact on the patient’s health status, as well as interfere with COPD management. Mortality The World Health Organization publishes mortality statistics for selected causes of death annually for all WHO regions; additional information is available from the WHO Evidence for Health Policy Department ( evidence). Data must be interpreted cautiously, however, because of inconsistent use of terminology for COPD. In the 10th revision of the ICD, deaths from COPD or chronic airways obstruction are included in the broad category of “COPD and allied conditions” (ICD-10 codes J42-46). Under-recognition and under-diagnosis of COPD still affect the accuracy of mortality data14,15 . Although COPD is often a primary cause of death, it is more likely to be listed as a contributory cause of death or omitted from the death certificate entirely16,504 . However, it is clear that COPD is one of the most important causes of death in most countries. The Global Burden of Disease Study projected that COPD, which ranked sixth as a cause of death in 1990, will become the third leading cause of death worldwide by 2020; a newer projection estimated COPD will be the fourth leading cause of death in 20305 . This increased mortality is mainly driven by the expanding epidemic of smoking, reduced mortality from other common causes of death (e.g. ischemic heart disease, infectious diseases), and aging of the world population. Economic Burden COPD is associated with significant economic burden. In the European Union, the total direct costs of respiratory disease are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (38.6 billion Euros) of this cost of respiratory disease17 . In the United States the estimated direct costs of COPD are $29.5 billion and the indirect costs $20.4 billion18 . COPD exacerbations account for the greatest proportion of the total COPD burden on the health care system. Not surprisingly, there is a striking direct relationship between the severity of COPD and the cost of care, and the distribution of costs changes as the disease progresses. For example, hospitalization and ambulatory oxygen costs soar as COPD severity increases. Any estimate of direct medical expenditures for home care under-represents the true cost of home care to society, because it ignores the economic value of the care provided to those with COPD by family members. In developing countries, direct medical costs may be less important than the impact of COPD on workplace and home productivity. Because the health care sector might not provide long-term supportive care services for severely COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  21. 21. 4 DEFINITION AND OVERVIEW disabled individuals, COPD may force two individuals to leave the workplace—the affected individual and a family member who must now stay home to care for the disabled relative. Since human capital is often the most important national asset for developing countries, the indirect costs of COPD may represent a serious threat to their economies. Social Burden Since mortality offers a limited perspective on the human burden of a disease, it is desirable to find other measures of disease burden that are consistent and measurable across nations. The authors of the Global Burden of Disease Study designed a method to estimate the fraction of mortality and disability attributable to major diseases and injuries using a composite measure of the burden of each health problem, the Disability-Adjusted Life Year (DALY)2,19,20 . The DALYs for a specific condition are the sum of years lost because of premature mortality and years of life lived with disability, adjusted for the severity of disability. In 1990, COPD was the twelfth leading cause of DALYs lost in the world, responsible for 2.1% of the total. According to the projections, COPD will be the seventh leading cause of DALYs lost worldwide in 20305 . Although cigarette smoking is the best-studied COPD risk factor, it is not the only one and there is consistent evidence from epidemiologic studies that nonsmokers may also develop chronic airflow limitation21-24 . Much of the evidence concerning risk factors for COPD comes from cross-sectional epidemiological studies that identify associations rather than cause-and-effect relationships. Although several longitudinal studies of COPD have followed groups and populations for up to 20 years25 , none has monitored the progression of the disease through its entire course, or has included the pre-and perinatal periods which may be important in shaping an individual’s future COPD risk. Thus, current understanding of risk factors for COPD is in many respects still incomplete. COPD results from a gene-environment interaction. Among people with the same smoking history, not all will develop COPD due to differences in genetic predisposition to the disease, or in how long they live. Risk factors for COPD may also be related in more complex ways. For example, gender may influence whether a person takes up smoking or experiences certain occupational or environmental exposures; socioeconomic status may be linked to a child’s birth weight (as it impacts on lung growth and development and in turn on susceptibility to develop the disease); and longer life expectancy will allow greater lifetime exposure to risk factors. Understanding the relationships and interactions among risk factors requires further investigation. Genes The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin26 , a major circulating inhibitor of serine proteases. Although alpha-1 antitrypsin deficiency is relevant to only a small part of the world’s population, it illustrates the interaction between genes and environmental exposures leading to COPD. A significant familial risk of airflow limitation has been observed in smoking siblings of patients with severe COPD27 , suggesting that genetic together with environmental factors could influence this susceptibility. Single genes such as the gene encoding matrix metalloproteinase 12 (MMP12) have been related to decline in lung function28 . Although several genome- wide association studies indicate a role of the gene for the alpha-nicotinic acetylcholine receptor as well as the hedge-hog interacting protein gene and possibly one or two others, there remains a discrepancy between findings from analyses of COPD and lung function as well as between genome-wide association study analyses and candidate gene analyses29-33 . Age and Gender Age is often listed as a risk factor for COPD. It is unclear if healthy aging as such leads to COPD or if age reflects the sum of cumulative exposures throughout life. In the past, most studies showed that COPD prevalence and mortality were greater among men than women but data from developed countries18,34 show that the prevalence of the disease is now almost equal in men and women, probably reflecting the changing patterns of tobacco smoking. Some studies have even suggested that women are more susceptible to the effects of tobacco smoke than men35-38 . Lung Growth and Development Lung growth is related to processes occurring during gestation, birth, and exposures during childhood and adolescence39,40 . Reduced maximal attained lung function (as measured by spirometry) may identify individuals who are at increased risk for the development of COPD41 . Any factor that affects lung growth during gestation and childhood has the potential for increasing an individual’s risk of developing COPD. For example, a large study and meta-analysis confirmed a positive association between birth weight and FEV1 in adulthood42 , and several studies have found an effect of early childhood lung infections. FACTORS THAT INFLUENCE DISEASE DEVELOPMENT AND PROGRESSION COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  22. 22. DEFINITION AND OVERVIEW 5 A study found that factors in early life termed “childhood disadvantage factors” were as important as heavy smoking in predicting lung function in early adult life43 . Exposure to Particles Across the world, cigarette smoking is the most commonly encountered risk factor for COPD. Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1 , and a greater COPD mortality rate than nonsmokers44 . Other types of tobacco (e.g., pipe, cigar, water pipe45 ) and marijuana46 are also risk factors for COPD47,48 . Passive exposure to cigarette smoke (also known as environmental tobacco smoke or ETS) may also contribute to respiratory symptoms49 and COPD50 by increasing the lung’s total burden of inhaled particles and gases51,52 . Smoking during pregnancy may also pose a risk for the fetus, by affecting lung growth and development in utero and possibly the priming of the immune system53,54 . Occupational exposures, including organic and inorganic dusts and chemical agents and fumes, are an underappreciated risk factor for COPD55-57 . An analysis of the large U.S. population-based NHANES III survey of almost 10,000 adults aged 30-75 years estimated the fraction of COPD attributable to work was 19.2% overall, and 31.1% among never-smokers58 . These estimates are consistent with a statement published by the American Thoracic Society that concluded that occupational exposures account for 10-20% of either symptoms or functional impairment consistent with COPD59 . The risk from occupational exposures in less regulated areas of the world is likely to be much higher than reported in studies from Europe and North America. Wood, animal dung, crop residues, and coal, typically burned in open fires or poorly functioning stoves, may lead to very high levels of indoor air pollution. Evidence continues to grow that indoor pollution from biomass cooking and heating in poorly ventilated dwellings is an important risk factor for COPD60-66 . Almost 3 billion people worldwide use biomass and coal as their main source of energy for cooking, heating, and other household needs, so the population at risk worldwide is very large63,67 . High levels of urban air pollution are harmful to individuals with existing heart or lung disease. The role of outdoor air pollution in causing COPD is unclear, but appears to be small when compared with that of cigarette smoking. It has also been difficult to assess the effects of single pollutants in long-term exposure to atmospheric pollution. However, air pollution from fossil fuel combustion, primarily from motor vehicle emissions in cities, is associated with decrements of respiratory function68 . The relative effects of short-term, high-peak exposures and long-term, low-level exposures are yet to be resolved. Socioeconomic Status Poverty is clearly a risk factor for COPD but the components of poverty that contribute to this are unclear. There is strong evidence that the risk of developing COPD is inversely related to socioeconomic status69 . It is not clear, however, whether this pattern reflects exposures to indoor and outdoor air pollutants, crowding, poor nutrition, infections, or other factors that are related to low socioeconomic status. Asthma/Bronchial Hyperreactivity Asthma may be a risk factor for the development of COPD, although the evidence is not conclusive. In a report from a longitudinal cohort of the Tucson Epidemiological Study of Airway Obstructive Disease, adults with asthma were found to have a twelve-fold higher risk of acquiring COPD over time than those without asthma, after adjusting for smoking70 . Another longitudinal study of people with asthma found that around 20% of subjects developed irreversible airflow limitation and reduced transfer coefficient71 , and in a longitudinal study self-reported asthma was associated with excess loss of FEV1 in the general population72 . In the European Community Respiratory Health Survey, bronchial hyperresponsiveness was second only to cigarette smoking as the leading risk factor for COPD, responsible for 15% of the population attributable risk (smoking had a population attributable risk of 39%)73 . The pathology of chronic airflow limitation in asthmatic nonsmokers and non-asthmatic smokers is markedly different, suggesting that the two disease entities may remain different even when presenting with similarly reduced lung function74 . However, clinically separating asthma from COPD may not be easy. Bronchial hyperreactivity can exist without a clinical diagnosis of asthma and has been shown to be an independent predictor of COPD in population studies75 as well as an indicator of risk of excess decline in lung function in patients with mild COPD76 . Chronic Bronchitis In the seminal study by Fletcher and coworkers, chronic bronchitis was not associated with decline in lung function77 . However, subsequent studies have found an association between mucus hypersecretion and FEV1 decline78 , and in younger adults who smoke the presence of chronic bronchitis is associated with an increased likelihood of developing COPD79,80 . Infections A history of severe childhood respiratory infection has been associated with reduced lung function and increased respiratory symptoms in adulthood39,73 . Susceptibility to COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  23. 23. 6 DEFINITION AND OVERVIEW infections plays a role in exacerbations of COPD but the effect on the development of the disease is less clear. HIV infection has been shown to accelerate the onset of smoking-related emphysema81 . Tuberculosis has been found to be a risk factor for COPD82,83 . In addition, tuberculosis is both a differential diagnosis to COPD and a potential comorbidity83,84 . Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic inflammatory response may induce parenchymal tissue destruction (resulting in emphysema), and disrupt normal repair and defense mechanisms (resulting in small airway fibrosis). These pathological changes lead to air trapping and progressive airflow limitation. A brief overview follows of the pathologic changes in COPD, their cellular and molecular mechanisms, and how these underlie physiologic abnormalities and symptoms characteristic of the disease85 Pathology Pathological changes characteristic of COPD are found in the airways, lung parenchyma, and pulmonary vasculature86 . The pathological changes include chronic inflammation, with increased numbers of specific inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair. In general, the inflammatory and structural changes in the airways increase with disease severity and persist on smoking cessation. Pathogenesis The inflammation in the respiratory tract of COPD patients appears to be a modification of the inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this amplified inflammation are not yet understood but may be genetically determined. Patients can clearly develop COPD without smoking, but the nature of the inflammatory response in these patients is unknown. Oxidative stress and an excess of proteinases in the lung further modify lung inflammation. Together, these mechanisms lead to the characteristic pathological changes in COPD. Lung inflammation persists after smoking cessation through unknown mechanisms, although autoantigens and persistent microorganisms may play a role87 . Oxidative Stress. Oxidative stress may be an important amplifying mechanism in COPD88 . Biomarkers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane) are increased in the exhaled breath condensate, sputum, and systemic circulation of COPD patients. Oxidative stress is further increased in exacerbations. Oxidants are generated by cigarette smoke and other inhaled particulates, and released from activated inflammatory cells such as macrophages and neutrophils. There may also be a reduction in endogenous antioxidants in COPD patients as a result of reduction in a transcription factor called Nrf2 that regulates many antioxidant genes89 . Protease-Antiprotease Imbalance. There is compelling evidence for an imbalance in the lungs of COPD patients between proteases that break down connective tissue components and antiproteases that protect against this. Several proteases, derived from inflammatory cells and epithelial cells, are increased in COPD patients. There is increasing evidence that they may interact with each other. Protease-mediated destruction of elastin, a major connective tissue component in lung parenchyma, is believed to be an important feature of emphysema and is likely to be irreversible. Inflammatory Cells. COPD is characterized by a specific pattern of inflammation involving increased numbers of CD8+ (cytotoxic) Tc1 lymphocytes present only in smokers that develop the disease85 . These cells, together with neutrophils and macrophages, release inflammatory mediators and enzymes and interact with structural cells in the airways, lung parenchyma and pulmonary vasculature90 . Inflammatory Mediators. The wide variety of inflammatory mediators that have been shown to be increased in COPD patients91 attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors)92 . Differences in Inflammation Between COPD and Asthma. Although both COPD and asthma are associated with chronic inflammation of the respiratory tract, there are differences in the inflammatory cells and mediators involved in the two diseases, which in turn account for differences in physiological effects, symptoms, and response to therapy74 . Some patients with COPD have features consistent with asthma and may have a mixed inflammatory pattern with increased eosinophils. Pathophysiology There is now a good understanding of how the underlying disease process in COPD leads to the characteristic physiologic abnormalities and symptoms. For example, inflammation and narrowing of peripheral airways leads to decreased FEV1 . Parenchymal destruction due to emphysema also contributes to airflow limitation and leads to decreased gas transfer. PATHOLOGY, PATHOGENESIS AND PATHOPHYSIOLOGY COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  24. 24. DEFINITION AND OVERVIEW 7 Airflow Limitation and Air Trapping. The extent of inflammation, fibrosis, and luminal exudates in small airways is correlated with the reduction in FEV1 and FEV1 /FVC ratio, and probably with the accelerated decline in FEV1 characteristic of COPD90 . This peripheral airway obstruction progressively traps air during expiration, resulting in hyperinflation. Although emphysema is more associated with gas exchange abnormalities than with reduced FEV1 , it does contribute to gas trapping during expiration. This is especially so as alveolar attachments to small airways are destroyed when the disease becomes more severe. Hyperinflation reduces inspiratory capacity such that functional residual capacity increases, particularly during exercise (dynamic hyperinflation), resulting in increased dyspnea and limitation of exercise capacity. These factors contribute to impairment of the intrinsic contractile properties of respiratory muscles; this results in upregulation of local pro-inflammatory cytokines. It is thought that hyperinflation develops early in the disease and is the main mechanism for exertional dyspnea93,94 . Bronchodilators acting on peripheral airways reduce air trapping, thereby reducing lung volumes and improving symptoms and exercise capacity93 . Gas Exchange Abnormalities. Gas exchange abnormalities result in hypoxemia and hypercapnia, and have several mechanisms in COPD. In general, gas transfer for oxygen and carbon dioxide worsens as the disease progresses. Reduced ventilation may also be due to reduced ventilatory drive. This may lead to carbon dioxide retention when it is combined with reduced ventilation due to a high work of breathing because of severe obstruction and hyperinflation coupled with ventilatory muscle impairment. The abnormalities in alveolar ventilation and a reduced pulmonary vascular bed further worsen the VA /Q abnormalities95 . Mucus Hypersecretion. Mucus hypersecretion, resulting in a chronic productive cough, is a feature of chronic bronchitis and is not necessarily associated with airflow limitation. Conversely, not all patients with COPD have symptomatic mucus hypersecretion. When present, it is due to an increased number of goblet cells and enlarged submucosal glands in response to chronic airway irritation by cigarette smoke and other noxious agents. Several mediators and proteases stimulate mucus hypersecretion and many of them exert their effects through the activation of epidermal growth factor receptor (EGFR)96 . Pulmonary Hypertension. Pulmonary hypertension may develop late in the course of COPD and is due mainly to hypoxic vasoconstriction of small pulmonary arteries, eventually resulting in structural changes that include intimal hyperplasia and later smooth muscle hypertrophy/ hyperplasia97 . There is an inflammatory response in vessels similar to that seen in the airways and evidence of endothelial cell dysfunction. The loss of the pulmonary capillary bed in emphysema may also contribute to increased pressure in the pulmonary circulation. Progressive pulmonary hypertension may lead to right ventricular hypertrophy and eventually to right-side cardiac failure. Exacerbations. Exacerbations of respiratory symptoms often occur in patients with COPD, triggered by infection with bacteria or viruses (which may coexist), environmental pollutants, or unknown factors. Patients with bacterial and viral episodes have a characteristic response with increased inflammation. During respiratory exacerbations there is increased hyperinflation and gas trapping, with reduced expiratory flow, thus accounting for the increased dyspnea98 . There is also worsening of VA /Q abnormalities, which can result in hypoxemia99 . Other conditions (pneumonia, thromboembolism, and acute cardiac failure) may mimic or aggravate an exacerbation of COPD. Systemic Features. It is increasingly recognized that many patients with COPD have comorbidities that have a major impact on quality of life and survival100 . Airflow limitation and particularly hyperinflation affect cardiac function and gas exchange101 . Inflammatory mediators in the circulation may contribute to skeletal muscle wasting and cachexia, and may initiate or worsen comorbidities such as ischemic heart disease, heart failure, osteoporosis, normocytic anemia, diabetes, metabolic syndrome, and depression. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  27. 27. 10 DIAGNOSIS AND ASSESSMENT KEY POINTS: • A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease. • Spirometry is required to make the diagnosis in this clinical context; the presence of a post-bronchodilator FEV1 /FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD. • The goals of COPD assessment are to determine the severity of the disease, including the severity of airflow limitation, the impact on the patient’s health status, and the risk of future events (such as exacerbations, hospital admissions, or death), in order to guide therapy. • Comorbidities occur frequently in COPD patients, including cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, and lung cancer. Given that they can occur in patients with mild, moderate and severe airflow limitation and influence mortality and hospitalizations independently, comorbidities should be actively looked for, and treated appropriately if present. DIAGNOSIS A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease (Table 2.1). Spirometry is required to make the diagnosis in this clinical context505 ; the presence of a post- bronchodilator FEV1 /FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD. The spirometric criterion for airflow limitation remains a post-bronchodilator fixed ratio of FEV1 /FVC < 0.70. This criterion is simple, independent of reference values, and has been used in numerous clinical trials forming the evidence base from which most of our treatment recommendations are drawn. Diagnostic simplicity and consistency are key for the busy non-specialist clinician. While post-bronchodilator spirometry is required for the diagnosis and assessment of severity of COPD, the degree of reversibility of airflow limitation (e.g., measuring FEV1 before and after bronchodilator or corticosteroids) is no longer recommended506 . The degree of reversibility has never been shown to add to the diagnosis, differential diagnosis with asthma, or to predicting the response to long-term treatment with bronchodilators or corticosteroids. The role of screening spirometry in the general population is controversial. Both FEV1 and FVC predict all-cause mortality independent of tobacco smoking, and abnormal lung function identifies a subgroup of smokers at increased risk for lung cancer. This has been the basis of an argument that screening spirometry should be employed as a global health assessment tool102,103 . However, there are no data to indicate that screening spirometry is effective in directing management decisions or in improving COPD outcomes in patients who are identified before the development of significant symptoms104 . Thus, GOLD advocates active case finding but not screening spirometry. The use of the fixed FEV1 /FVC ratio to define airflow limitation will result in more frequent diagnosis of COPD in the elderly105 , and less frequent diagnosis in adults younger than 45 years106 , especially of mild disease, compared to using a cutoff based on the lower limit of normal (LLN) values for FEV1 /FVC. These LLN values are based on the normal distribution and classify the bottom 5% of the healthy population as abnormal. From a scientific perspective it is difficult to determine which of these criteria is correct to diagnose COPD107 , and no studies exist CHAPTER 2: DIAGNOSIS AND ASSESSMENT Table 2.1. Key Indicators for Considering a Diagnosis of COPD Consider COPD, and perform spirometry, if any of these indicators are present in an individual over age 40. These indicators are not diagnostic themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is required to establish a diagnosis of COPD. Dyspnea that is: Progressive (worsens over time). Characteristically worse with exercise. Persistent. Chronic cough: May be intermittent and may be unproductive. Chronic sputum production: Any pattern of chronic sputum production may indicate COPD. History of exposure to risk factors: Tobacco smoke (including popular local preparations). Smoke from home cooking and heating fuels. Occupational dusts and chemicals. Family history of COPD COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  28. 28. DIAGNOSIS AND ASSESSMENT 11 comparing clinical diagnosis based on the two approaches. However, LLN values are highly dependent on the choice of valid reference equations using post-bronchodilator FEV1 , and neither longitudinal studies validating the use of the LLN nor studies using reference equations in populations where smoking is not the major cause of COPD are available. The risk of misdiagnosis and over-treatment of individual patients using the fixed ratio as a diagnostic criterion is limited, as spirometry is only one parameter for establishing the clinical diagnosis of COPD, the others being symptoms and risk factors. Symptoms The characteristic symptoms of COPD are chronic and progressive dyspnea, cough, and sputum production that can be variable from day-to-day507,508 . Chronic cough and sputum production may precede the development of airflow limitation by many years. Individuals, particularly those exposed to COPD risk factors, who present with these symptoms should be examined to search for an underlying cause(s) and appropriate interventions taken. Conversely, significant airflow limitation may develop without chronic cough and sputum production. Although COPD is defined on the basis of airflow limitation, in practice the decision to seek medical help (and so permit the diagnosis to be made) is usually determined by the impact of a symptom on a patient’s daily life. A person may seek medical attention either because of chronic symptoms or because of a first exacerbation. Dyspnea. Dyspnea, a cardinal symptom of COPD, is a major cause of disability and anxiety associated with the disease. Typical COPD patients describe their dyspnea as a sense of increased effort to breathe, heaviness, air hunger, or gasping108 . However, the terms used to describe dyspnea vary both by individual and by culture109 . Cough. Chronic cough, often the first symptom of COPD to develop110 , is frequently discounted by the patient as an expected consequence of smoking and/or environmental exposures. Initially, the cough may be intermittent, but later is present every day, often throughout the day. The chronic cough in COPD may be unproductive111 . In some cases, significant airflow limitation may develop without the presence of a cough. Table 2.2 lists some of the other causes of chronic cough. Sputum production. COPD patients commonly raise small quantities of tenacious sputum after coughing bouts. Regular production of sputum for 3 or more months in 2 consecutive years (in the absence of any other conditions that may explain it) is the epidemiological definition of chronic bronchitis112 , but this is a somewhat arbitrary definition that does not reflect the range of sputum production in COPD patients. Sputum production is often difficult to evaluate because patients may swallow sputum rather than expectorate it, a habit subject to significant cultural and gender variation. Patients producing large volumes of sputum may have underlying bronchiectasis. The presence of purulent sputum reflects an increase in inflammatory mediators113 , and its development may identify the onset of a bacterial exacerbation114 . Wheezing and Chest Tightness. Wheezing and chest tightness are nonspecific symptoms that may vary between days, and over the course of a single day. Audible wheeze may arise at a laryngeal level and need not be accompanied by auscultatory abnormalities. Alternatively, widespread inspiratory or expiratory wheezes can be present on listening to the chest. Chest tightness often follows exertion, is poorly localized, is muscular in character, and may arise from isometric contraction of the intercostal muscles. An absence of wheezing or chest tightness does not exclude a diagnosis of COPD, nor does the presence of these sypmtoms confirm a diagnosis of asthma. Additional Features in Severe Disease. Fatigue, weight loss and anorexia are common problems in patients with severe and very severe COPD115 . They are prognostically important116 and can also be a sign of other diseases (e.g., tuberculosis, lung cancer), and therefore should always be investigated. Cough syncope occurs due to rapid increases in intrathoracic pressure during prolonged attacks of coughing. Coughing spells may also cause rib fractures, which are sometimes asymptomatic. Ankle swelling may be the only symptomatic pointer to the development of cor pulmonale. Symptoms of depression and/or anxiety merit specific enquiry in the clinical history because they are common in COPD117 and are associated with increased risk of exacerbations and poorer health status. Table 2.2. Causes of Chronic Cough Intrathoracic • Chronic obstructive pulmonary disease • Asthma • Lung cancer • Tuberculosis • Bronchiectasis • Left heart failure • Interstitial lung disease • Cystic fibrosis • Idiopathic cough Extrathoracic • Chronic allergic rhinitis • Upper Airway Cough Syndrome (UACS) • Gastroesophageal reflux • Medication (e.g., ACE inhibitors) COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  29. 29. 12 DIAGNOSIS AND ASSESSMENT Medical History A detailed medical history of a new patient known or thought to have COPD should assess: • Patient’s exposure to risk factors, such as smoking and occupational or environmental exposures • Past medical history, including asthma, allergy, sinusitis, or nasal polyps; respiratory infections in childhood; other respiratory diseases • Family history of COPD or other chronic respiratory disease • Pattern of symptom development: COPD typically develops in adult life and most patients are conscious of increased breathlessness, more frequent or prolonged “winter colds,” and some social restriction for a number of years before seeking medical help • History of exacerbations or previous hospitalizations for respiratory disorder: Patients may be aware of periodic worsening of symptoms even if these episodes have not been identified as exacerbations of COPD • Presence of comorbidities, such as heart disease, osteoporosis, musculoskeletal disorders, and malignancies that may also contribute to restriction of activity118 • Impact of disease on patient’s life, including limitation of activity, missed work and economic impact, effect on family routines, feelings of depression or anxiety, well being and sexual activity • Social and family support available to the patient • Possibilities for reducing risk factors, especially smoking cessation Physical Examination Although an important part of patient care, a physical examination is rarely diagnostic in COPD. Physical signs of airflow limitation are usually not present until significant impairment of lung function has occurred119,120 , and their detection has a relatively low sensitivity and specificity. A number of physical signs may be present in COPD, but their absence does not exclude the diagnosis. Spirometry Spirometry is the most reproducible and objective measurement of airflow limitation available. Peak expiratory flow measurement alone cannot be reliably used as the only diagnostic test, despite its good sensitivity, because of its weak specificity121 . Good quality spirometric measurement is possible in any health care setting and all health care workers who care for COPD patients should have access to spirometry. Table 2.3 summarizes some of the factors needed to achieve accurate test results. Spirometry should measure the volume of air forcibly exhaled from the point of maximal inspiration (forced vital capacity, FVC) and the volume of air exhaled during the first second of this maneuver (forced expiratory volume in one second, FEV1 ), and the ratio of these two measurements (FEV1 /FVC) should be calculated. The ratio between FEV1 and slow vital capacity (VC), FEV1 /VC, is sometimes measured instead of the FEV1 /FVC ratio. This will often lead to lower values of the ratio, especially in pronounced airflow limitation; however, the cut-off point of 0.7 should still be applied. Spirometry measurements are evaluated by comparison with reference values122 based on age, height, sex, and race. Figure 2.1A shows a normal spirometry tracing; Figure 2.1B a spirometry tracing typical of a patient with obstructive disease. Patients with COPD typically show a decrease in both FEV1 and FVC. The goals of COPD assessment are to determine the severity of the disease, its impact on the patient’s health status and the risk of future events (such as exacerbations, hospital admissions or death), in order to, eventually, guide therapy. Table 2.3. Considerations in Performing Spirometry Preparation • Spirometers need calibration on a regular basis. • Spirometers should produce hard copy or have a digital display of the expiratory curve to permit detection of technical errors or have an automatic prompt to identify an unsatisfactory test and the reason for it. • The supervisor of the test needs training in its effective performance. • Maximal patient effort in performing the test is required to avoid underestimation of values and hence errors in diagnosis and management. Bronchodilation • Possible dosage protocols are 400 mcg beta2 -agonist, 160 mcg anticholinergic, or the two combined122 . FEV1 should be measured 10-15 minutes after a short-acting beta2 -agonist is given, or 30-45 minutes after a short-acting anticholinergic or a combination. Performance • Spirometry should be performed using techniques that meet published standards123 . • The expiratory volume/time traces should be smooth and free from irregularities. • The recording should go on long enough for a volume plateau to be reached, which may take more than 15 seconds in severe disease. • Both FVC and FEV1 should be the largest value obtained from any of 3 technically satisfactory curves and the FVC and FEV1 values in these three curves should vary by no more than 5% or 150 ml, whichever is greater. • The FEV1 /FVC ratio should be taken from the technically acceptable curve with the largest sum of FVC and FEV1 . Evaluation • Spirometry measurements are evaluated by comparison of the results with appropriate reference values based on age, height, sex, and race. • The presence of a postbronchodilator FEV1 /FVC < 0.70 confirms the presence of airflow limitation. ASSESSMENT OF DISEASE COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  30. 30. DIAGNOSIS AND ASSESSMENT 13 To achieve these goals, COPD assessment must consider the following aspects of the disease separately: • Current level of patient’s symptoms • Severity of the spirometric abnormality • Exacerbation risk • Presence of comorbidities Assessment of Symptoms In the past, COPD was viewed as a disease largely characterized by breathlessness. A simple measure of breathlessness such as the Modified British Medical Research Council (mMRC) Questionnaire (Table 2.4) was considered adequate for assessment of symptoms, as the mMRC relates well to other measures of health status91 and predicts future mortality risk92 . However, it is now recognized that COPD has multiple symptomatic effects151 . For this reason, a comprehensive symptom assessment is recommended rather than just a measure of breathlessness. The most comprehensive disease-specific health-related quality of life or health status questionnaires such as the CRQ236 and SGRQ347 are too complex to use in routine practice, but two shorter comprehensive measures (COPD Assessment Test, CAT and COPD Control Questionnaire, CCQ) have been developed and are suitable. COPD Assessment Test (CAT). The COPD Assessment Test is an 8-item unidimensional measure of health status impairment in COPD124 . It was developed to be applicable worldwide and validated translations are available in a wide range of languages. The score ranges from 0-40, correlates very closely with the SGRQ, and has been extensively documented in numerous publications548 (http://www. COPD Control Questionnaire (CCQ). The COPD Control Questionnaire is a 10 item self-administered questionnaire developed to measure clinical control in patients with COPD509, 510 . Although the concept of “control” in COPD remains controversial, the CCQ is short and easy to administer. It is reliable and responsive, is available in a range of languages, and has been validated ( Choice of Cut Points The CAT and CCQ provide a measure of the symptomatic impact of COPD but do not categorize patients into lower and higher symptoms for the purpose of treatment. The SGRQ is the most widely documented comprehensive measure; scores less than 25 are uncommon in diagnosed COPD patients131,549 and scores ≥ 25 are very uncommon in healthy persons549 . In clinical trials of long-acting bronchodilator medications 201,210, 516, 550-553 , the baseline weighted mean SGRQ score was 44, and one standard deviation below the mean was 26. Therefore, it is 1 2 3 4 5 6 1 2 3 4 Volume,liters Time, seconds 5 1 FEV1 = 4L FVC = 5L FEV1/FVC = 0.8 Volume,liters Time, seconds 5 4 3 2 1 1 2 3 4 5 6 FEV1 = 1.8L FVC = 3.2L FEV1/FVC = 0.56 Obstructive Figure 2.1B. Spirometry - Obstructive DiseaseFigure 2.1A. Spirometry - Normal Trace Table 2.4. Modified Medical Research Council Questionnaire for Assessing the Severity of Breathlessness PLEASE TICK IN THE BOX THAT APPLIES TO YOU (ONE BOX ONLY) mMRC Grade 0. I only get breathless with strenuous exercise. □ mMRC Grade 1. I get short of breath when hurrying on the level □ or walking up a slight hill. mMRC Grade 2. I walk slower than people of the same age on the □ level because of breathlessness, or I have to stop for breath when walking on my own pace on the level. mMRC Grade 3. I stop for breath after walking about 100 meters or □ after a few minutes on the level. mMRC Grade 4. I am too breathless to leave the house or I am □ breathless when dressing or undressing. COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE
  31. 31. 14 DIAGNOSIS AND ASSESSMENT recommended that a symptom score equivalent to SGRQ score ≥ 25 should be used as the cut-point for considering regular treatment for symptoms including breathlessness, particularly since this corresponds to the range of severity seen in patients recruited to the trials that provide the evidence base for treatment recommendations. The equivalent cut-point for the CAT is 10123, 554 . The equivalent cut-point for the CCQ has yet to be finally determined, but appears to be in the range 1.0 - 1.5. An equivalent mMRC score cannot be calculated because a simple breathlessness cut-point cannot equate to a comprehensive symptom score cut-point. The great majority of patients with an SGRQ of 25 or more will have an mMRC of 2 or more; however patients with mMRC < 2 may also have a number of other COPD symptoms. While use of an mMRC ≥ 2 as a cut-point may be adequate for breathlessness assessment, it will also categorize a number of patients with symptoms other than breathlessness as having “few symptoms.” For this reason, the use of a comprehensive symptom assessment is recommended. However, because use of the mMRC is still widespread, an mMRC of ≥ 2 is still included as a cut-point for separating “less breathlessness” from “more breathlessness.” However, users are cautioned that assessment of other symptoms is required554,555 . Spirometric Assessment Table 2.5 shows the classification of airflow limitation severity in COPD. Specific spirometric cut-points are used for purposes of simplicity. Spirometry should be performed after the administration of an adequate dose of a short-acting inhaled bronchodilator in order to minimize variability. However, there is only a weak correlation between FEV1 , symptoms and impairment of a patient’s health- related quality of life. This is illustrated in Figure 2.2 in which health-related quality of life is plotted against post-bronchodilator FEV1 126,127 with the GOLD spirometric classification superimposed. The figure illustrates that, within any given category, patients may have anything between relatively well preserved to very poor health status. For this reason, formal symptomatic assessment is also required. Assessment of Exacerbation Risk An exacerbation of COPD is defined as an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication128-130 . The rate at which exacerbations occur varies greatly between patients131,512 . The best predictor of having frequent exacerbations (2 or more exacerbations per year) is a history of previous treated events132 . In addition, worsening airflow limitation is associated with an increasing prevalence of exacerbations and risk of death. Hospitalization for a COPD exacerbation is associated with a poor prognosis with increased risk of death556 . A large body of data has been accumulated in patients131,152 classified using GOLD spirometric grading systems. These show an increase in risk of exacerbations, hospitalization and death with worsening of airflow limitation. The data in Table 2.6 are derived from prospectively collected data from large medium-term clinical trials132-134 . They are not precise estimates that apply to each patient, but they illustrate clearly the increased risk of exacerbations and death between spirometric levels. Roughly, although up to 20% of GOLD 2 (Moderate aiflow limitation) patients may experience frequent exacerbations requiring treatment with antibiotics and/or systemic corticosteroids132 , the risk of exacerbations significantly increases in GOLD 3 (Severe) Table 2.5. Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV1 ) In patients with FEV1 /FVC < 0.70: GOLD 1: Mild FEV1 ≥ 80% predicted GOLD 2: Moderate 50% ≤ FEV1 < 80% predicted GOLD 3: Severe 30% ≤ FEV1 < 50% predicted GOLD 4: Very Severe FEV1 < 30% predicted Figure 2.2. Relationship Between Health-related Quality of Life, Post-bronchodilator FEV1 and GOLD Spirometric Classification (Adapted from Jones127 ) COPYRIGHTED M ATERIAL -DO NOT ALTER OR REPRODUCE